The epidermis is a stratified epithelium consisting of numerous cell layers. The principal cell type of the epidermis is the keratinocyte. Keratinocytes are responsible for the resistance of the skin to physical and chemical injury and for its impermeability to water. These functions are carried out primarily by the outermost layer of keratinocytes, termed "corneocytes," which have undergone programmed cell death. Corneocytes consist of a skeletal framework of keratin filaments surrounded by a special envelope that is found in no other cells within the body. This envelope consists of proteins ("corneocyte proteins") stabilized by inter-molecular isopeptide bonds (Rice and Green (1977), Cell, 11:417-422). The bonds are introduced by an enzyme, calcium-activated keratinocyte transglutaminase (Rice and Green (1979), Cell, 18:681-694). As skin ages, the epidermis atrophies with accompanying diminution of its physical resistance.
The basal layer of the epidermis contains proliferating keratinocytes. When keratinocytes leave the basal layer, they begin to undergo terminal differentiation. When they reach the granular layer, the concentration of calcium ions inside the keratinocytes rises, resulting in activation of transglutaminase. The envelope precursor proteins, which at this stage are located just beneath the plasma membrane, are crosslinked by transglutaminase (Rice and Green (1979), ibid.; Greenberg et al. (1991) FASEB, 5:3071-3077) and the resulting envelope becomes thoroughly insoluble, even in the presence of detergents and reducing agents (Green (1977), Cell, 11:405-416; Hohl (1990), Dermatologica, 180:201-211). This envelope is the most resistant structure of the skin since keratin filaments, even though they are stabilized by disulfide bonds, can be dissolved by a combination of detergent and reducing agent. Transglutaminase and its crosslinked products are also present in hair and nails (Rice et al., Keratinocyte Handbook, (in press)).